Process for the preparation of intermediate of dolutegravir

ABSTRACT

The present invention provides a novel processes for preparation of methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyiridine-2-carboxylate using novel intermediates.

This application claims the benefit of Indian Provisional Patent Application No. 2996/CHE/2013, filed on Jul. 4, 2013, which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention provides a novel processes for preparation of methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyiridine-2-carboxylate using novel intermediates.

BACKGROUND OF THE INVENTION

Dolutegravir, chemically (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide and has the structural formula I:

Dolutegravir is an experimental new drug under investigation for the treatment of HIV infection. Dolutegravir is an integrase inhibitor. Also known as S/GSK1349572 or, the drug is under development by GlaxoSmithKline (GSK).

The chemical formula of methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyiridine-2-carboxylate of formula II:

Dolutegravir and its processes were disclosed in U.S. Pat. No. 8,129,385 ('385 patent). The synthetic procedure is illustrated in scheme I, below:

According to the '385 patent also described a process for the methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyiridine-2-carboxylate. The synthetic procedure is illustrated in scheme II, below:

Processes for the preparation of dolutegravir were disclosed in International patent application publications. WO 2010/011812, WO 2010/068253 and WO 2010/011819, and also disclosed in European patent application. 2412709.

The methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyiridine-2-carboxylate is a key intermediate for the preparation of Dolutegravir.

It has been found that the methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyiridine-2-carboxylate produced according to the prior art procedures involves higher number of chemical steps and results in low yields. According to the present invention methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyiridine-2-carboxylate can be obtained in higher yields and in fewer number of reaction steps than the prior art processes.

We have found a novel processes for the preparation of methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyiridine-2-carboxylate using novel intermediate.

The processes of present invention are simple, inexpensive and reproducible and are well suited on an industrial scale.

Thus, an object of the present invention is to provide a novel processes for preparing methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyiridine-2-carboxylate using novel intermediate.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a novel process for the preparation of methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyiridine-2-carboxylate of formula II, which comprises:

-   a) treating the 3-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde with     trimethyl orthoformate in the presence of camphorsulfonic acid and a     suitable solvent to give     3-(benzyloxy)-2-(dimethoxymethyl)-4H-pyran-4-one of formula III; -   b) reacting the 3-(benzyloxy)-2-(dimethoxymethyl)-4H-pyran-4-one     obtained in step (a) with methanolic ammonia in the presence of an     alcoholic solvent to give     3-(benzyloxy)-2-(dimethoxymethyl)pyridin-4(1H)-one of formula IV; -   c) bromonating the     3-(benzyloxy)-2-(dimethoxymethyl)pyridin-4(1H)-one obtained in     step (b) with N-bromosuccinimide in the presence of a chlorinated     solvent to give     3-(benzyloxy)-5-bromo-2-(dimethoxymethyl)pyridin-4(1H)-one of     formula V; -   d) treating the     3-(benzyloxy)-5-bromo-2-(dimethoxymethyl)pyridin-4(1H)-one obtained     in step (c) with n-butyllithium in the presence of dimethylformamide     and an ether solvent to give     5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde     of formula VI; -   e) reacting the     5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde     obtained in step (d) with sulfamic acid and sodium chlorite in a     suitable solvent to give     5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic     acid of formula VII; -   f) condensing the     5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic     acid obtained in step (e) with 2,4-difluorobenzylamine in the     presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide     hydrochloride, hydroxybenzotriazole and tertiary amine in a suitable     solvent to give     5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide     of formula VIII; -   g) condensing the     5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide     obtained in step (f) with allyl bromide in the presence of a base     and dimethylformamide to give     1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide     of formula XI; -   h) treating the     1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide     obtained in step (g) with formic acid in a ketonic solvent to give     1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-formyl-4-oxo-1,4-dihydropyridine-3carboxamide     of formula XII; -   i) reacting the     1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-formyl-4-oxo-1,4-dihydropyridine-3-carboxamide     obtained in step (h) with sulfamic acid and sodium chlorite in a     suitable solvent to give     1-allyl-3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1,4dihydropyridine-2-carboxylic     acid of formula XIII; and -   j) methylating the     1-allyl-3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic     acid with methyl iodide in the presence of a base and     dimethylformamide to give methyl     3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate     of formula II.

In another aspect, the present invention provides a novel process for the preparation of methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyiridine-2-carboxylate of formula II, which comprises:

-   a) treating the 3-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde with     trimethyl orthoformate in the presence of camphorsulfonic acid and a     suitable solvent to give     3-(benzyloxy)-2-(dimethoxymethyl)-4H-pyran-4-one of formula III; -   b) reacting the 3-(benzyloxy)-2-(dimethoxymethyl)-4H-pyran-4-one     obtained in step (a) with methanolic ammonia in the presence of an     alcoholic solvent to give     3-(benzyloxy)-2-(dimethoxymethyl)pyridin-4(1H)-one of formula IV; -   c) bromonating the     3-(benzyloxy)-2-(dimethoxymethyl)pyridin-4(1H)-one obtained in     step (b) with N-bromosuccinimide in the presence of a chlorinated     solvent to give     3-(benzyloxy)-5-bromo-2-(dimethoxymethyl)pyridin-4(1H)-one of     formula V; -   d) treating the     3-(benzyloxy)-5-bromo-2-(dimethoxymethyl)pyridin-4(1H)-one obtained     in step (c) with n-butyllithium in the presence of dimethylformamide     and an ether solvent to give     5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde     Formula VI; -   e) condensing the     5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde     obtained in step (d) with allyl bromide in the presence of a base     and dimethylformamide to give     1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde     of formula IX; -   f) reacting the     1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde     obtained in step (e) with sulfamic acid and sodium chlorite in a     suitable solvent to give     1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3carboxylic     acid of formula X; -   g) condensing the     1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic     acid obtained in step (f) with 2,4-difluorobenzylamine in the     presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide     hydrochloride, hydroxybenzotriazole and tertiary amine in a suitable     solvent to give     1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide     of formula XI; -   h) treating the     1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide     obtained in step (g) with formic acid in a ketonic solvent to give     1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-formyl-4-oxo-1,4-dihydropyridine-3-carboxamide     of formula XII; -   i) reacting the     1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-formyl-4-oxo-1,4-dihydropyridine-3-carboxamide     obtained in step (h) with sulfamic acid and sodium chlorite in a     suitable solvent to give     1-allyl-3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic     acid of formula XIII; and -   j) methylating the     1-allyl-3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic     acid with methyl iodide in the presence of a base and     dimethylformamide to give methyl     3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate     of formula II.

In another aspect, the present invention provides a novel compound of 3-(benzyloxy)-2-(dimethoxymethyl)-4H-pyran-4-one of formula III:

In another aspect, the present invention provides a novel compound of 3-(benzyloxy)-2-(dimethoxymethyl)pyridin-4(1H)-one of formula IV:

In another aspect, the present invention provides a novel compound of 3-(benzyloxy)-5-bromo-2-(dimethoxymethyl)pyridin-4(1H)-one of formula V:

In another aspect, the present invention provides a novel compound of 5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde of formula VI:

In another aspect, the present invention provides a novel compound of 5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid of formula VII:

In another aspect, the present invention provides a novel compound of 5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide of formula VIII:

In another aspect, the present invention provides a novel compound of 1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde of formula IX:

In another aspect, the present invention provides a novel compound of 1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid of formula X:

In another aspect, the present invention provides a novel compound of 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide of formula XI:

In another aspect, the present invention provides a novel compound of 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-formyl-4-oxo-1,4-dihydropyridine-3-carboxamide of formula XII:

In another aspect, the present invention provides a novel compound of 1-allyl-3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid of formula XIII:

DETAILED DESCRIPTION OF THE INVENTION

As used herein the term “room temperature” refers to a temperature of about 25° C. to about 35° C.

According to one aspect of the present invention, there is provided a novel process for the preparation of methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyiridine-2-carboxylate of formula II, which comprises:

-   a) treating the 3-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde with     trimethyl orthoformate in the presence of camphorsulfonic acid and a     suitable solvent to give     3-(benzyloxy)-2-(dimethoxymethyl)-4H-pyran-4-one of formula III; -   b) reacting the 3-(benzyloxy)-2-(dimethoxymethyl)-4H-pyran-4-one     obtained in step (a) with methanolic ammonia in the presence of an     alcoholic solvent to give     3-(benzyloxy)-2-(dimethoxymethyl)pyridin-4(1H)-one of formula IV; -   c) bromonating the     3-(benzyloxy)-2-(dimethoxymethyl)pyridin-4(1H)-one obtained in     step (b) with N-bromosuccinimide in the presence of a chlorinated     solvent to give     3-(benzyloxy)-5-bromo-2-(dimethoxymethyl)pyridin-4(1H)-one of     formula V; -   d) treating the     3-(benzyloxy)-5-bromo-2-(dimethoxymethyl)pyridin-4(1H)-one obtained     in step (c) with n-butyllithium in the presence of dimethylformamide     and an ether solvent to give     5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde     of formula VI; -   e) reacting the     5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde     obtained in step (d) with sulfamic acid and sodium chlorite in a     suitable solvent to give     5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic     acid of formula VII; -   f) condensing the     5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic     acid obtained in step (e) with 2,4-difluorobenzylamine in the     presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide     hydrochloride, hydroxybenzotriazoie and tertiary amine in a suitable     solvent to give     5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide     of formula VIII; -   g) condensing the     5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide     obtained in step (f) with allyl bromide in the presence of a base     and dimethylformamide to give     1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide     of formula XI; -   h) treating the     1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide     obtained in step (g) with formic acid in a ketonic solvent to give     1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-formyl-4-oxo-1,4-dihydropyridine-3carboxamide     of formula XII; -   i) reacting the     1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-formyl-4-oxo-1,4-dihydropyridine-3-carboxamide     obtained in step (h) with sulfamic acid and sodium chlorite in a     suitable solvent to give     1-allyl-3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic     acid of formula XIII; and -   j) methylating the     1-allyl-3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic     acid with methyl iodide in the presence of a base and     dimethylformamide to give methyl     3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate     of formula II.

The suitable solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate, methyl formate, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol and isobutyl alcohol. More preferably the suitable solvents are methylene chloride and methanol.

Preferably the alcoholic solvent used in step (b) may be a solvent or a mixture of solvents selected from methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol and isobutyl alcohol, and more preferably the alcoholic solvent is methanol.

The chlorinated solvent used in step (c) may preferably be a solvent or a mixture of solvents selected from methylene chloride, ethylene dichloride, chloroform and carbon tetrachloride, and more preferably the chlorinated solvent is methylene chloride.

Preferably the ether solvent used in step (d) may preferably be a solvent or a mixture of solvents selected from tetrahydrofuran, diethyl ether, diisopropyl ether and tert-butyl methyl ether. More preferably the ether solvent is tetrahydrofuran.

The suitable solvent used in step (e) may preferably be a solvent or a mixture of solvents selected from water, acetone, diethyl ketone, methyl ethyl ketone, methyl propyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate, methyl formate, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol and isobutyl alcohol. More preferably the suitable solvents are water, acetone and methanol.

Preferably the suitable solvent used in step (f) may preferably be a solvent or a mixture of solvents selected from dimethylformamide, dimethyl sulfoxide, dimethylacetamide, acetone, diethyl ketone, methyl ethyl ketone, methyl propyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate, methyl formate, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol and isobutyl alcohol. More preferably the suitable solvents are dimethylformamide and dimethyl sulfoxide.

The tertiary amine used in step (f) may preferably be selected from N,N-diisopropylethylamine, triethylamine or trimethylamine, and more preferably the tertiary amine is triethylamine.

The base used in step (g) may preferably be an organic base or an inorganic base. More preferably the base is inorganic base selected from sodium carbonate, sodium hydroxide, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, calcium carbonate or calcium bicarbonate. Still more preferably the base is cesium carbonate.

Preferably the ketonic solvent used in step (h) may be a solvent or a mixture of solvents selected from acetone, diethyl ketone, methyl ethyl ketone, methyl propyl ketone, methyl isobutyl ketone and methyl tert-butyl ketone, and more preferably the ketonic solvent is acetone.

The suitable solvent used in step (i) may preferably be a solvent or a mixture of solvents selected from water, acetone, diethyl ketone, methyl ethyl ketone, methyl propyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate, methyl formate, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol and isobutyl alcohol. More preferably the suitable solvents are water, acetone and methanol.

Preferably the base used in step (j) may be an organic base or an inorganic base. More preferably the base is inorganic base selected from sodium carbonate, sodium hydroxide, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, calcium carbonate or calcium bicarbonate. Still more preferably the base is sodium carbonate or sodium bicarbonate.

According to another aspect of the present invention, there is provided a novel process for the preparation of methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyiridine-2-carboxylate of formula II, which comprises:

-   a) treating the 3-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde with     trimethyl orthoformate in the presence of camphorsulfonic acid and a     suitable solvent to give     3-(benzyloxy)-2-(dimethoxymethyl)-4H-pyran-4-one of formula III; -   b) reacting the 3-(benzyloxy)-2-(dimethoxymethyl)-4H-pyran-4-one     obtained in step (a) with methanolic ammonia in the presence of an     alcoholic solvent to give     3-(benzyloxy)-2-(dimethoxymethyl)pyridin-4(1H)-one of formula IV; -   c) bromonating the     3-(benzyloxy)-2-(dimethoxymethyl)pyridin-4(1H)-one obtained in     step (b) with N-bromosuccinimide in the presence of a chlorinated     solvent to give     3-(benzyloxy)-5-bromo-2-(dimethoxymethyl)pyridin-4(1H)-one of     formula V; -   d) treating the     3-(benzyloxy)-5-bromo-2-(dimethoxymethyl)pyridin-4(1H)-one obtained     in step (c) with n-butyllithium in the presence of dimethylformamide     and an ether solvent to give     5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde     Formula VI; -   e) condensing the     5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde     obtained in step (d) with allyl bromide in the presence of a base     and dimethylformamide to give     1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde     of formula IX; -   f) reacting the     1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde     obtained in step (e) with sulfamic acid and sodium chlorite in a     suitable solvent to give     1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic     acid of formula X; -   g) condensing the     1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic     acid obtained in step (f) with 2,4-difluorobenzylamine in the     presence of 1-(3-dimethylaminopropy;)-3-ethylcarbodiimide     hydrochloride, hydroxybenzotriazole and tertiary amine in a suitable     solvent to give     1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide     of formula XI; -   h) treating the     1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide     obtained in step (g) with formic acid in a ketonic solvent to give     1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-formyl-4-oxo-1,4-dihydropyridine-3-carboxamide     of formula XII; -   i) reacting the     1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-formyl-4-oxo-1,4-dihydropyridine-3-carboxamide     obtained in step (h) with sulfamic acid and sodium chlorite in a     suitable solvent to give     1-allyl-3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic     acid of formula XIII; and -   j) methylating the     1-allyl-3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic     acid with methyl iodide in the presence of a base and     dimethylformamide to give methyl     3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate     of formula II.

The suitable solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate, methyl formate, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol and isobutyl alcohol. More preferably the suitable solvents are methylene chloride and methanol.

Preferably the alcoholic solvent used in step (b) may be a solvent or a mixture of solvents selected from methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol and isobutyl alcohol, and more preferably the alcoholic solvent is methanol.

The chlorinated solvent used in step (c) may preferably be a solvent or a mixture of solvents selected from methylene chloride, ethylene dichloride, chloroform and carbon tetrachloride, and more preferably the chlorinated solvent is methylene chloride.

Preferably the ether solvent used in step (d) may preferably be a solvent or a mixture of solvents selected from tetrahydrofuran, diethyl ether, diisopropyl ether and tert-butyl methyl ether. More preferably the ether solvent is tetrahydrofuran.

The base used in step (e) may preferably be an organic base or an inorganic base. More preferably the base is inorganic base selected from sodium carbonate, sodium hydroxide, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, calcium carbonate or calcium bicarbonate. Still more preferably the base is cesium carbonate.

The suitable solvent used in step (f) may preferably be a solvent or a mixture of solvents selected from water, acetone, diethyl ketone, methyl ethyl ketone, methyl propyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate, methyl formate, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol and isobutyl alcohol. More preferably the suitable solvents are water, acetone and methanol.

Preferably the suitable solvent used in step (g) may preferably be a solvent or a mixture of solvents selected from dimethylformamide, dimethyl sulfoxide, dimethylacetamide, acetone, diethyl ketone, methyl ethyl ketone, methyl propyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate, methyl formate, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol and isobutyl alcohol. More preferably the suitable solvents are dimethylformamide and dimethyl sulfoxide.

The tertiary amine used in step (g) may preferably be selected from N,N-diisopropylethylamine, triethylamine or trimethylamine, and more preferably the tertiary amine is triethylamine.

Preferably the ketonic solvent used in step (h) may be a solvent or a mixture of solvents selected from acetone, diethyl ketone, methyl ethyl ketone, methyl propyl ketone, methyl isobutyl ketone and methyl tert-butyl ketone, and more preferably the ketonic solvent is acetone.

The suitable solvent used in step (i) may preferably be a solvent or a mixture of solvents selected from water, acetone, diethyl ketone, methyl ethyl ketone, methyl propyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate, methyl formate, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol and isobutyl alcohol. More preferably the suitable solvents are water, acetone and methanol.

Preferably the base used in step (j) may be an organic base or an inorganic base. More preferably the base is inorganic base selected from sodium carbonate, sodium hydroxide, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, calcium carbonate or calcium bicarbonate. Still more preferably the base is sodium carbonate or sodium bicarbonate.

As a specific example of the process for the preparation of methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyiridine-2-carboxylate of formula II may be represented by the following scheme 1:

As a specific example of the process for the

preparation of methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyiridine-2-carboxylate of formula II may be represented by the following scheme 2:

According to another aspect of the present invention, there is provided a novel compound of 3-(benzyloxy)-2-(dimethoxymethyl)-4H-pyran-4-one of formula III:

According to another aspect of the present invention, there is provided a novel compound of 3-(benzyloxy)-2-(dimethoxymethyl)pyridin-4(1H)-one of formula IV:

According to another aspect of the present invention, there is provided a novel compound of 3-(benzyloxy)-5-bromo-2-(dimethoxymethyl)pyridin-4(1H)-one of formula V:

According to another aspect of the present invention, there is provided a novel compound of 5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde of formula VI:

According to another aspect of the present invention, there is provided a novel compound of 5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid of formula VII:

According to another aspect of the present invention, there is provided a novel compound of 5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide of formula VIII:

According to another aspect of the present invention, there is provided a novel compound of 1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde of formula IX:

According to another aspect of the present invention, there is provided a novel compound of 1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid of formula X:

According to another aspect of the present invention, there is provided a novel compound of 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide of formula XI:

According to another aspect of the present invention, there is provided a novel compound of 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-formyl-4-oxo-1,4-dihydropyridine-3-carboxamide of formula XII:

According to another aspect of the present invention, there is provided a novel compound of 1-allyl-3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid of formula XIII:

The invention will now be further described by the following examples, which are illustrative rather than limiting.

EXAMPLES Example 1 Preparation of 3-(benzyloxy)-2-methyl-4H-pyran-4-one

Maltol (100 gm) was dissolved in acetonitrile (600 ml) and potassium carbonate (153 gm) and benzyl bromide (116 ml) was added to the solution. The contents were heated to 80° C. and stirred for 3 hours. The reaction mass was cooled to room temperature and filtered. The solvent was distilled off from the filtrate thus obtained under reduced pressure to obtain 155 gm of 3-(benzyloxy)-2-methyl-4H-pyran-4-one.

Example 2 Preparation of 3-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde

To a 3-(benzyloxy)-2-methyl-4H-pyran-4-one (80 gm) was added bromo benzene (800 ml) and selenium oxide (82 gm) at room temperature. The reaction mixture was heated to 160° C. and stirred for 24 hours. The reaction mass was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure to obtain 54 gm of 3-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde.

Example 3 Preparation of 3-(benzyloxy)-2-(dimethoxymethyl)-4H-pyran-4-one of Formula III

3-(Benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde (54 gm) was dissolved in a mixture of methylene chloride and methanol (1:1; 540 ml). Trimethyl orthoformate (51 ml) and camphorsulfonic acid (11 gm) were added to the solution and the reaction mixture was heated to 60° C. The reaction mass was stirred for 3 hours at 60° C. and the methanol solvent was distilled off, and then diluted with saturated aqueous sodium bicarbonate solution (250 ml) and extracted with methylene chloride. Combined organic layers were dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain 50 gm of 3-(benzyloxy)-2-(dimethoxymethyl)-4H-pyran-4-one.

¹H NMR (300 MHz, CDCl₃): δ 7.73 (d, J=5.7 Hz, 1H), 7.39-7.36 (m, 5H), 6.43 (d, J=5.7 Hz, 1H), 5.25 (s, 1H), 5.24 (s, 2H), 3.3 (s, 6H).

Example 4 Preparation of 3-(benzyloxy)-2-(dimethoxymethyl)pyridin-4(1H)-one of Formula IV

3-(Benzyloxy)-2-(dimethoxymethyl)-4H-pyran-4-one (50 gm) was dissolved in methanol (100 ml) and methanolic ammonia solution (250 ml) was then added. The reaction mixture was stirred for 12 hours at room temperature and concentrated under reduced pressure to obtain 32 gm of 3-(benzyloxy)-2-(dimethoxymethyl)pyridin-4(1H)-one.

¹H NMR (300 MHz, CDCl₃): δ 9.34 (bs, 1H), 7.44-7.3 (m, 6H), 6.5 (d, J=6.9 Hz, 1H), 5.28 (bs, 3H), 3.26 (s, 6H).

Example 5 Preparation of 3-(benzyloxy)-5-bromo-2-(dimethoxymethyl)pyridin-4(1H)-one of Formula V

To a 3-(benzyloxy)-2-(dimethoxymethyl)pyridin-4(1H)-one (32 gm) was added methylene chloride (320 ml) and N-bromosuccinimide (23 gm) at 0° C. The reaction mixture was stirred for 3 hours at 0° C. to room temperature. The reaction mixture was added water (300 ml) and extracted with methylene chloride. Combined organic layers were dried with anhydrous sodium sulfate and concentrated to obtain a residual solid. The residual solid thus obtained was purified by silica gel column chromatography with a mixture of ethyl acetate and n-hexane (1:2) to obtain 28.5 gm of 3-(benzyloxy)-5-bromo-2-(dimethoxymethyl)pyridin-4(1H)-one.

¹H NMR (300 MHz, CDCl₃): δ 8.94 (bs, 1H), 7.82 (s, 1H), 7.48-7.45 (m, 2H), 7.39-7.29 (m, 3H), 5.3-5.28 (m, 3H), 3.29 (s, 6H).

Example 6 Preparation of 5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde of Formula VI

To a 3-(benzyloxy)-5-bromo-2-(dimethoxymethyl)pyridin-4(1H)-one (8.5 gm) was added dry tetrahydrofuran (128 ml) and a solution of n-butyllithium in hexane (24 ml in 2.5 molar hexane) slowly at −78° C. under nitrogen atmosphere. The reaction mixture was stirred for 45 minutes at −78° C. and dimethylformamide (3.7 ml) was then added at −78° C. The reaction mixture was stirred for 45 minutes at −78° C. and heated to −10° C. The reaction mass was quenched with aqueous ammonium chloride and extracted with ethyl acetate. Combined organic layers were dried with anhydrous sodium sulfate and concentrated to obtain a residual solid. The residual solid thus obtained was purified by neutral alumina column chromatography with ethyl acetate and n-hexane (1:1) to obtain 4.8 gm of 5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde.

¹H NMR (300 MHz, CDCl₃): δ 10.36 (s, 1H), 8.18 (s, 1H), 7.46-7.31 (m, 5H), 5.34 (s, 2H), 5.31 (s, 1H), 3.33 (s, 6H).

Example 7 Preparation of 5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic Acid of Formula VII

5-(Benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde (8 gm) was dissolved in a mixture of acetone and water (1:1, 80 ml) at 0° C. To the solution was added sulfamic acid (6.4 gm) and sodium chlorite (4.8 gm) at 0° C. The reaction mixture was stirred for 5 hours at 0° C. to room temperature and the acetone solvent was distilled off, and then diluted with 1N hydrochloric acid and extracted with methylene chloride. Combined organic layers were dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain 5.8 gm of 5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid.

¹H NMR (300 MHz, CDCl₃): δ 15.84 (bs, 1H), 12.86 (bs, 1H), 8.24 (d, J=6.6 Hz, 1H), 7.48-7.33 (m, 5H), 5.45 (s, 1H), 5.22 (s, 2H), 3.29 (s, 6H).

Example 8 Preparation of 5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide of Formula VIII

To 5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (4.4 gm) was added dimethylformamide (66 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4 gm) and hydroxybenzotriazole (1.8 gm) sequentially at 0° C. under nitrogen atmosphere. To the reaction mixture was added triethylamine (7.7 ml) and 2,4-difluorobenzylamine (2.2 ml) at 0° C. and stirred for 48 hours at room temperature. The reaction mixture was diluted with water (50 ml) and then extracted with methylene chloride. Combined organic layers were dried with anhydrous sodium sulfate and concentrated to obtain a residual solid. The residual solid was purified by silica gel column chromatography with a mixture of ethyl acetate and n-hexane (2:3) to obtain 3.5 gm of 5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide.

¹H NMR (300 MHz, CDCl₃): δ 10.6 (bs, 1H), 9.23 (bs, 1H), 8.55 (s, 1H), 7.48-7.32 (m, 6H), 6.86-6.77 (m, 2H), 5.31 (s, 1H), 5.28 (s, 2H), 4.66 (d, J=6 Hz, 2H), 3.29 (s, 6H).

Example 9 Preparation of 1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde of Formula IX

5-(Benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde (10 gm) was dissolved in dimethylformamide (60 ml) and cesium carbonate (13 gm) and allyl bromide (4.2 ml) were then added. The reaction mixture was heated to 80° C. and stirred for 1 hour. The reaction mass was cooled to room temperature, and then diluted with water (100 ml) and extracted with ethyl acetate. Combined organic layers were dried with anhydrous sodium sulfate and concentrated to obtain 9.6 gm of 1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde.

¹H NMR (300 MHz, CDCl₃): δ 10.38 (s, 1H), 7.93 (s, 1H), 7.4-7.29 (m, 5H), 5.93-5.85 (m, 1H), 5.47 (s, 1H), 5.32-5.18 (m, 4H), 4.76-4.63 (m, 2H), 3.21 (s, 6H).

Example 10 Preparation of 1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic Acid of Formula X

1-Allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde (13 gm) was dissolved in a mixture of acetone and water (1:1, 130 ml) at 0° C. To the solution was added sulfamic acid (9.2 gm) and sodium chlorite (6.8 gm) at 0° C. The reaction mixture was stirred for 3 hours at 0° C. to room temperature and the acetone solvent was distilled off, and then diluted with 1N hydrochloric acid and extracted with ethyl acetate. Combined organic layers were dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain 5.5 gm of 1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid.

¹H NMR (300 MHz, CDCl₃): δ 15.42 (bs, 1H), 8.38 (s, 1H), 7.42-7.28 (m, 5H), 5.91-5.85 (m, 1H), 5.55 (s, 1H), 5.36-5.22 (m, 4H), 4.85 (d, J=6.0 Hz, 2H), 3.27 (s, 6H).

Example 11 Preparation of 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide of Formula XI

5-(Benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (1.4 gm) as obtained in example 8 was dissolved in dimethylformamide (8 ml) and cesium carbonate (1.2 gm) and allyl bromide (0.4 ml) were then added. The reaction mixture was heated to 80° C. and stirred for 1 hour. The reaction mass was cooled to room temperature, and then diluted with water (20 ml) and extracted with ethyl acetate. Combined organic layers were dried with anhydrous sodium sulfate and concentrated to obtain 1.1 gm of 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide.

¹H NMR (300 MHz, CDCl₃): δ 10.6 (bs, 1H), 8.42(s, 1H), 7.41-7.36 (m, 6H), 6.83-6.79 (m, 2H), 5.9-5.88 (m, 1H), 5.51 (s, 1H), 5.28-5.19 (m, 4H), 4.84-4.7 (m, 2H), 4.64 (d, J=6.0 Hz, 2H), 3.24 (s, 6H).

Example 12 Preparation of 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide of Formula XI

To a 1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (5.5 gm) as obtained in example 10 was added dimethylformamide (33 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.4 gm) and hydroxybenzotriazole (2.1 gm) sequentially at 0° C. under nitrogen atmosphere. Triethylamine (8.6 ml) and 2,4-difluorobenzylamine (2.2 ml) were added to the reaction mixture and stirred for 48 hours at room temperature. The reaction mixture was diluted with water (50 ml) and extracted with methylene chloride. Combined organic layers were dried with anhydrous sodium sulfate and concentrated to obtain a residual solid. The residual solid was purified by silica gel column chromatography with a mixture of ethyl acetate and n-hexane (2:3) to obtain 2 gm of 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide.

Example 13 Preparation of 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-formyl-4-oxo-1,4-dihydropyridine-3-carboxamide of Formula XII

1-Allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (1.1 gm) was dissolved in acetone (4.4 ml) and added formic acid (98%; 4.4 ml) at room temperature. The reaction mixture was heated to 80° C. and stirred for 3 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution at 0° C. and extracted with ethyl acetate. Combined organic layers were dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain 0.9 gm of 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-formyl-4-oxo-1,4-dihydropyridine-3-carboxamide.

¹H NMR (300 MHz, CDCl₃): δ 10.34 (bs, 1H), 9.96 (s, 1H), 8.41 (s, 1H), 7.42-7.32 (m, 6H), 6.88-6.79 (m, 2H), 5.87-5.78 (m, 1H), 5.5 (s, 2H), 5.19 (d, J=10.5 Hz, 1H), 4.96-4.85 (m, 3H), 4.66 (d, J=5.7 Hz, 2H).

Example 14 Preparation of 1-allyl-3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic Acid of Formula XIII

1-Allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-formyl-4-oxo-1,4-dihydropyridine-3-carboxamide (0.9 gm) was dissolved in a mixture of acetone and water (1:1; 9 ml) at 0° C. To the solution was added sulfamic acid (0.49 gm) and sodium chlorite (0.37 gm) at 0° C. The reaction mixture was stirred for 3 hours at 0° C. to room temperature and the acetone solvent was distilled off, and then diluted with 1N hydrochloric acid and extracted with ethyl acetate. Combined organic layers were dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain 0.8 gm of 1-allyl-3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid.

¹H NMR (300 MHz, DMSO): δ 10.43 (t, J=5.7 Hz, 1H), 8.54 (s, 1H), 7.47-7.23 (m, 7H), 7.11-7.06 (m, 1H), 6.02-5.93 (m, 1H), 5.3 (d, J=9.9 Hz, 1H), 5.24-5.09 (m, 3H), 4.75 (d, J=5.4 Hz, 2H), 4.55 (d, J=5.7 Hz, 2H).

Example 15 Preparation of Methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate of Formula II

To a 1-allyl-3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid (3 gm) was added N-methylpyrrolidone (15 ml), sodium bicarbonate (1.7 gm) and methyl iodide (0.84 ml) at 0° C. The reaction mixture was allowed to room temperature and stirred for 2 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. Combined organic layers were dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2 gm of methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate.

¹H NMR (300 MHz, CDCl₃): δ 10.44 (t, J=5.7 Hz, 1H), 8.43 (s, 1H), 7.39-7.34 (m, 6H), 6.86-6.77 (m, 2H), 5.93-5.8 (m, 1H), 5.35 (d, J=10.5 Hz, 1H), 5.29-5.19 (m, 3H), 4.64 (d, J=6.0 Hz, 2H), 4.53 (d, J=5.7 Hz, 2H), 3.76 (s, 3H).

Example 16 Preparation of Methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-1-(2,3-dihydroxypropyl)-4-oxo-1,4-dihydropyridine-2-carboxylate

Methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate (0.7 gm) was dissolved in a mixture acetone and water (9:1, 14 ml) at 0° C. To the solution was added N-methylmorpholine N-oxide (1.05 gm) and a solution 2% osmium tetroxide in toluene (3.8 ml) at 0° C. The reaction mixture was allowed to room temperature and stirred for 5 hours, and then quenched with saturated sodium bisulfate and extracted with ethyl acetate. Combined organic layers were dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain 0.6 gm of methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-1-(2,3-dihydroxypropyl)-4-oxo-1,4-dihydropyridine-2-carboxylate.

¹H NMR (300 MHz, CDCl₃): δ10.58 (t, J=5.7 Hz, 1H), 8.48 (s, 1H), 7.42-7.28 (m, 6H), 6.86-6.77 (m, 2H), 5.28-5.19 (m, 2H), 4.63-4.59 (m, 2H), 4.12-3.93 (m, 3H), 3.89 (s, 3H), 3.72-3.63(m, 1H), 3.58-3.48 (m, 1H).

Example 17 Preparation of Methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate

To a methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-1-(2,3-dihydroxypropyl)-4-oxo-1,4-dihydropyridine-2-carboxylate (0.6 gm) was added methylene chloride (0.6 gm), saturated sodium bicarbonate (0.6 ml) and sodium periodate (1.28 gm) at 0° C. The reaction mixture was allowed to room temperature and stirred for 14 hours. The reaction mass was filtered through celite bed and then concentrated to obtain 0.5 gm of methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate.

Example 18 Preparation of (4R,12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxamide

Methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate (0.5 gm) was dissolved in toluene (5 ml) and methanol (0.5 ml). (R)-3-Aminobutane-1-ol (0.17 gm) and acetic acid (0.5 ml) were added to the solution at room temperature. The contents were heated to 120° C. and stirred for 4 hours. The reaction mass was cooled to 0° C., and then quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. Combined organic layers were dried with anhydrous sodium sulfate and concentrated to obtain a residual solid. The residual solid was purified by silica gel column chromatography with a mixture of ethyl acetate and n-hexane (1:3) to obtain 0.2 gm of (4R,12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxamide.

¹H NMR (300 MHz, CDCl₃): δ 10.41 (bs, 1H), 8.35 (s, 1H), 7.63-7.61 (m, 2H), 7.38-7.33 (m, 5H), 6.86-6.78 (m, 2H), 5.33-5.25 (m, 2H), 5.17 (t, J=5.7 Hz, 1H), 5.03-4.99 (m, 1H), 4.64 (d, J=5.7 Hz, 2H), 4.25-4.19 (m, 1H), 4.16-4.07 (m, 1H), 3.97-3.95 (m, 2H), 2.29-2.12 (m, 1H), 1.54-1.49 (m, 1H), 1.34 (d, J=7.2 Hz, 3H).

Example 19 Preparation of Dolutegravir

(4R,12aS)-7-(Benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxamide (0.4 gm) was dissolved in a mixture of ethyl acetate and ethanol (10:1, 4.2 ml) and 10% palladium on carbon (0.042 gm) was then added. To the reaction mass was applied hydrogen gas via a balloon for 30 minutes. The resultant reaction mass was filtered through celite bed and concentrated to obtain a residual solid. The residual solid was purified by silica gel column chromatography with a mixture of chloroform and methanol (99:1) to obtain 0.06 gm of dolutegravir.

¹H NMR (300 MHz, DMSO): δ 12.5 (s, 1H), 10.35 (t, J=5.7 Hz, 1H), 8.5 (s, 1H), 7.42-7.34 (m, 1H), 7.27-7.21 (m, 1H), 7.1-7.03 (m, 1H), 5.45 (t, J=4.8 Hz, 1H), 4.81-4.77 (m, 1H), 4.6-4.5 (m, 3H), 4.34 (dd, J=5.7, 13.8 Hz, 1H), 4.07-3.99 (m, 1H), 3.9-3.88 (m, 1H), 2.05-1.96 (m, 1H), 1.56-1.52 (m, 1H), 1.33 (d, J=6.9 Hz, 3H). 

We claim:
 1. A process for the preparation of methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine -2carboxylate, which comprises: a) treating the 3-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde with trimethyl orthoformate in the presence of camphorsulfonic acid and a suitable solvent to give 3-(benzyloxy)-2-(dimethoxymethyl)-4H-pyran-4-one of formula III; b) reacting the 3-(benzyloxy)-2-(dimethoxymethyl)-4H-pyran-4-one obtained in step (a) with methanolic ammonia in the presence of an alcoholic solvent to give 3-(benzyloxy)-2-(dimethoxymethyl)pyridin-4(1H)-one of formula IV; c) bromionating the 3-(benzyloxy)-2-(dimethoxymethyl)pyridin-4(1H)-one obtained in step (b) with N-bromosuccinimide in the presence of a chlorinated solvent to give 3-(benzyloxy)-5-bromo-2-(dimethoxymethyl)pyridin-4(1H)-one of formula V; d) treating the 3-(benzyloxy)-5-bromo-2-(dimethoxymethyl)pyridin-4(1H)-one obtained in step (c) with n-butyllithium in the presence of dimethylformamide and an ether solvent to give 5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde of formula VI; e) reacting the 5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde obtained in step (d) with sulfamic acid and sodium chlorite in a suitable solvent to give 5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid of formula VII; f) condensing the 5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid obtained in step (e) with 2,4-difluorobenzylamine in the presence of 1-(3 -dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride, hydroxybenzotriazole and tertiary amine in a suitable solvent to give 5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo- 1,4-dihydropyridine-3-carboxamide of formula VIII; g) condensing the 5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide obtained in step (f) with allyl bromide in the presence of a base and dimethylformamide to give 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo- 1,4-dihydropyridine-3 -carboxamide of formula XI; h) treating the 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide obtained in step (g) with formic acid in a ketonic solvent to give 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-formyl-4-oxo-1,4-dihydropyridine-3-carboxamide of formula XII; i) reacting the 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-formyl-4-oxo-1,4-dihydropyridine-3-carboxamide obtained in step (h) with sulfamic acid and sodium chlorite in a suitable solvent to give 1-allyl-3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid of formula XIII; and j) methylating the 1-allyl-3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid with methyl iodide in the presence of a base and dimethylformamide to give methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate.
 2. A process for the preparation of methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4- dihydropyridine-2-carboxylate which comprises: a) treating the 3-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde with trimethyl orthoformate in the presence of camphorsulfonic acid and a suitable solvent to give 3-(benzyloxy)-2-(dimethoxymethyl)-4H-pyran-4-one of formula III; b) reacting the 3-(benzyloxy)-2-(dimethoxymethyl)-4H-pyran-4-one obtained in step (a) with methanolic ammonia in the presence of an alcoholic solvent to give 3-(benzyloxy)-2-(dimethoxymethyl)pyridin-4(1H)-one of formula IV; c) bromionating the 3-(benzyloxy)-2-(dimethoxymethyl)pyridin-4(1H)-one obtained in step (b) with N-bromosuccinimide in the presence of a chlorinated solvent to give 3-(benzyloxy)-5-bromo-2-(dimethoxymethyl)pyridin-4(1H)-one of formula V; d) treating the 3-(benzyloxy)-5-bromo-2-(dimethoxymethyl)pyridin-4(1H)-one obtained in step (c) with n-butyllithium in the presence of dimethylformamide and an ether solvent to give 5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde Formula VI; e) condensing the 5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde obtained in step (d) with allyl bromide in the presence of a base and dimethylformamide to give 1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde of formula IX; f) reacting the 1 - allyl-5-(benz yloxy)-6-(dimethoxymethyl)-4-oxo- 1,4-dihydropyridine-3-carbaldehyde obtained in step (e) with sulfamic acid and sodium chlorite in a suitable solvent to give 1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid of formula X; g) condensing the 1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid obtained in step (f) with 2,4-difluorobenzylamine in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, hydroxybenzotriazole and tertiary amine in a suitable solvent to give 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo- 1,4-dihydropyridine-3-carboxamide of formula XI; h) treating the 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide obtained in step (g) with formic acid in a ketonic solvent to give 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-formyl-4-oxo-1,4-dihydropyridine-3-carboxamide of formula XII; i) reacting the 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-formyl-4-oxo-1,4-dihydropyridine-3-carboxamide obtained in step (h) with sulfamic acid and sodium chlorite in a suitable solvent to give 1-allyl-3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid of formula XIII; and j) methylating the 1-allyl-3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid with methyl iodide in the presence of a base and dimethylformamide to give methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate. 